It has been noted that there are a number of biologically active phenolic compounds present in wine, particularly red wine. Such compounds include, for example, catechin, epicatechin, quercetin, rutin, trans-resveratrol, cis-resveratrol, cis-resveratrol glucoside and trans-resveratrol glucoside. See, e.g., Goldberg et al. (1996) Anal Chem. 68:1688-1694. These compounds have been shown to protect low-density lipoproteins against oxidation. The resveratrol isomers, in particular, have been found to promote vascular relaxation through the generation of nitric oxide by the endothelium, and to modulate eicosanoid synthesis in a manner that suggests use in preventing coronary artery occlusion and consequently acute and chronic ischemic heart disease, including myocardial infarction. Id. at pp. 1688-89). This discovery appears to explain the studies demonstrating that moderate consumption of red wine tends to have a protective effect against heart disease. Bertelli et al. (1995) Inst. J. Tiss. Reac. XVII(1):1-3. 
Resveratrol (3,5,4′-trihydroxystilbene) has been identified as a constituent not only of grape skins (Soleas et al. (1995) Am. J. Enol. Vitic. 46(3):346-352) but has also been found to be present in ground nuts, eucalyptus, and other plant species. Goldberg et al. (1995), Am. J. Enol. Vitic. 46(2):159-165. A great deal of interest has been focused on the compound's antifungal activity and its correlation with resistance to fungal infection. Id at 159. Resveratrol may be obtained commercially (typically as the trans isomer, e.g. from the Sigma Chemical Company, St. Louis, Mo.), or it may be isolated from wine or grape skins, or it may be chemically synthesized. Synthesis is typically carried out by a Wittig reaction linking two substituted phenols through a styrene double bond, as described by Moreno-Manas et al. (1985) Anal. Quim 81:157-61 and subsequently modified by others (Jeandet et al. (1991) Am. J. Enol. Vitic. 42:41-46; Goldberg et al. (1994) Anal. Chem. 66: 3959-63).
There are more studies concerning trans-resveratrol than the cis isomer; however, the cis isomer appears to be equally important from a biological standpoint. Numerous uses have been proposed and evaluated for the resveratrol isomers. Jang et al. (1997) Science 275:218-220, show that resveratrol has cancer chemopreventive activity in assays representing three major stages of carcinogenesis. That is, the authors found that the compound: (1) acted as an antioxidant and antimutagen and induced phase II drug-metabolizing enzymes; (2) mediated anti-inflammatory effects and inhibited cyclooxygenase and hydroperoxidase; and (3) induced human promyelocytic leukemia cell differentiation. In addition, as noted above, resveratrol has been extensively studied for its correlation to the cardiovascular utility of red wine. See, e.g., Bertelli et al., supra; Pace-Asciak et al. (1995), Clinica Chimica Acta 235:207-2191; and Frankel et al. (Apr. 24, 1993), The Lancet 341:1104. Neurologic uses have also been proposed (Lee et al. (1994), Society for Neuroscience Abstracts 20(1-2): 1648). More recently resveratrol has been shown to inhibit COX-2 transcription (Subbaramaiah et al. (1998) J. Biol. Chem. 273:21875-82; Martinez et al. (2000) Biochem. Pharmacol. 59:865-70), as well as inhibiting COX-1 enzymatic activity (Jang et al. (1997) Science 275:218-20), suggesting that resveratrol exerts an effect on transcription by affecting transcription factors, in addition to NSAID-like direct inhibition of COX enzymatic activity. Recent evidence suggests that macrolide antibiotics have a steroid-sparing antiinflammatory effect that is independent of their antibiotic activity and any effect on steroid metabolism (Cazzola et al. (2000) Monaldi Arch. Chest Dis. 55(3):231-6). The mechanism of macrolide reduction of bronchial hyperresponsiveness in asthmatics suggested by the evidence resembles the mechanism suggested by Jang et al. (2000), supra, a combination of inhibition of COX and increased synthesis of antiinflammatory cytokines, inhibiting initial chemotaxis of PMNs and the mixed lymphocyte response which ultimately results in eosinophilic inflammation seen in bronchial inflammation (Cazzola et al.(2000), supra).
In addition, resveratrol has found to be useful as a cancer chemopreventive agent. Known cancer chemopreventive agents include nonsteroidal antiinflammatory drugs (NSAIDs) such as indomethacin, aspirin, piroxicam, and sulindac, all of which inhibit cyclooxygenase, abbreviated hereafter as COX. A COX inhibitory activity is important in cancer chemoprevention because COX catalyzes the conversion of arachidonic acid to proinflammatory substances, such as prostaglandins, which can stimulate tumor cell growth and suppress immune surveillance. Plescia et al. (1975) Proc. Natl. Acad. Sci. USA. 72:1848; Goodwin (1984) Am. J. Med. 77:7. In addition, COX can activate carcinogens to forms that damage genetic material. Zenser et al. (1983) J. Pharmacol. Exp. Ther. 227:545; Wild et al. (1987) Carcinogenesis 8:541. Investigators have searched for new cancer chemopreventive agents by evaluating hundreds of plant extracts for a potential to inhibit COX. An extract derived from Cassia quinquangulata Rich. (Leguminosae) was identified as a potent COX inhibitor, and on the basis of bioassay-guided fractionation, trans-resveratrol was identified as the active compound. See Mannila et al. (19983) Phytochemistry 33:813, and Jayatilake et al. (1993) J. Nat. Prod. 5:1805.
To date, however, administration of resveratrol to treat inflammatory respiratory disorders is unknown. The present invention is premised on the unexpected finding that administration of resveratrol is extremely effective in treating inflammatory respiratory disorders, and is even more effective than oral, parenteral or pulmonary administration of corticosteroids.